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  • 1. How Might Basic Research on Low Dose Ionizing Radiation Influence Future Radiation Protection Programs William F. Morgan, Ph.D., D.Sc. Biological Sciences Division Pacific Northwest National Laboratory Richland, Washington USA
  • 2. Disclosures: Member of NCRP, ICRP and consultant for UNSCEAR - vested interest in this issue. But these are my opinions! Outline of presentation: Why it is important My research interests Future directions
  • 3. Mans Radiation Burden Air travel Testing fallout Cosmic rays TV & luminous Air (radon) watches Building material Nuclear power Water plants (20%) Food Radioactive waste Earth Diagnostic & therapeutic radiation* *> 200 million procedures/year (USA), 2 billion worldwide
  • 4. Computerized Tomography (10-30 mGy)
  • 5. Hair Loss From Excessive Dose Of A CT Angiogram
  • 6. CT Over-Exposure To A Young Patient Fell from bed and complained of neck pain the following morning Plain x-rays and then a CT scan of neck ordered by ER CT table did not index (move) and radiologic technologist manually instituted 151 slices over a period of more than 1 hour The patient was successfully rescanned by another technician About 2-3 hours after the first CT attempt he developed a red line around his face at the level of the 151 CT scan slices
  • 7. http://www.news.com.au/travel/news/naked- scanners-may-increase-cancer-risk US scientists are warning that radiation from controversial full- body airport scanners has been dangerously underestimated and could lead to an increased risk of skin cancer - particularly in children.
  • 8. This is why we have radiation protection programs and what radiation protection is all about! So where does the information regarding the health effects of ionizing radiation come from?
  • 9. Most of our understanding of radiation effects comes following a single acute exposure
  • 10. Radiation Effects Research Foundation (Hiroshima) a unique resource ~ 43% survivors still alive In the laboratory acute exposures practical and convenient Effect ? Radiation Dose
  • 11. Chernobyl, 1986 Protracted exposure (contamination)
  • 12. Research Interests Understanding effects of exposure to low dose (<100mGy), low dose rate ionizing radiation, the potential consequences of such exposure(s) and how to translate these data to radiation risk.
  • 13. Questions In the Context Of Radiation Protection How to extrapolate biological effects at low doses to risk? Are extrapolations from “high dose” acute exposures appropriate when human exposure is primarily chronic low dose exposure?
  • 14. The dilemma for radiation protection: what is the scientific basis for radiation standards to protect the public from exposures to low levels of ionizing radiation (<0.1 Sv) where there are considerable uncertainties in the epidemiological data. Radiation Related Cancer Risk A-bomb Survivor data Supra-linearity LNT Sub-linearity Background .01 .05 .1 1.0 4.0 10 100 Dose (Sv) Hormesis
  • 15. Radiation Protection Considerations Science is only one input to risk management What are the other inputs? Tradition Not scaring people Politics Social values Economic considerations Technological considerations We have a long legacy of mistrust to deal with! Plus some widely diverging opinions Hormesis - tolerance - acceptance - total denial
  • 16. Ionizing radiation Has The Potential To Cause Detrimental Effects: All radiation is bad and should be eliminated or reduced to a level as low as reasonably achievable (ALARA).
  • 17. On the other hand - complex biological systems have physiological barriers against damage and disease. Primary damage linear with dose, secondary damage not. Cellular processes block damage propagation to clinical disease.
  • 18. The Radiendocrinator (ca. 1930) Gold plated Radiendocrinator sold in its velvet lined pocket for $150. Beta- gamma GM detector ~ 200 mR/hr.
  • 19. Societies Perception of Risk Differs 21
  • 20. Epidemiology versus Biology Epidemiology is fraught with uncertainties…..So what is the biological data (presumably the mechanisms) that can help us understand the potential effects of exposure to ionizing radiation?
  • 21. The Current Paradigm For Risk Genetics Environment Diet Lifestyle Any exposure has the potential for risk
  • 22. Conventional paradigm for radiation effects
  • 23. In addition to targeted effects we must consider the impact of non-targeted effects Targeted cell Secreted / shed factors Survives and gap junction proliferates communication Bystander cell 25
  • 24. Radiation-Induced Genomic Instability Increased rate of genomic alterations in the progeny of irradiated cells Manifests as: chromosomal rearrangements micronuclei aneuploidy Irradiation delayed mutation (spectrum different) gene amplification cell killing Non clonal - not necessarily a fixed genetic change that is passed on.
  • 25. Clonally expand Irradiate Clonally expand Metaphase analysis of clonally expanded cells
  • 26. Radiation-Induced Instability Can Occur In Non-Targeted Cells: Instability observed in cells not traversed by an alpha particle Kadhim et al. Nature 355, 738-40 (1992) Shielded grid experiment Lorrimore et al. PNAS 95, 5730-3 (1998) secreted factor? cell to cell gap junction communication*? dead / dying cells*? *Not in our cell system
  • 27. Radiation Induced Bystander Effects: Effects observed in cells that were not irradiated but were “bystanders” at the time of irradiation Single cell microbeam irradiation 1 cell irradiated Single  particle
  • 28. Radiation induced bystander effects: Effects observed in cells that were not irradiated but were “bystanders” at the time of irradiation Single cell microbeam irradiation gene expression mutation 1 cell irradiated transformation micronuclei cell killing Why?
  • 29. Bystander effects in an in vivo human skin model (3D). Belyakov et al. PNAS 102, 14203-7 (2005) Beneficial? Eliminating damaged or initiated cells Detrimental? Inducing damage in non-irradiated cells
  • 30. Abscopal “Anti-Tumor” Effects In Vivo 5 x 10Gy Implanted 12 x 2Gy LLC cells fractionated Significant delay in LLC cell growth. Camphausen et al. Cancer Res. 63, 1990-1993 (2003)
  • 31. 76 year old male with back pain Abscopal Thoracic and abdominal CT scans thoracic vertebral bone metastasis Effects: and hepatocellular carcinoma 36Gy to the bone mass regression of hepatic lesions Ohba et al. Gut 43, 575-577, (1998) Retrospective analysis of serum concentration s of IL-1 beta, IL-2, IL-4, IL-6, HGF, and TNF-alpha
  • 32. Precedent For Secreted Factor(s) In Humans - Clastogenic Factors
  • 33. Clastogenic Factors In Plasma From: Accidentally irradiated individuals Goh & Sumner, Radiation Res. 35, 171-181 (1968) Therapeutically irradiated individuals Hollowell & Littlefield, PSEBM. 129, 240-244 (1968) A-bomb survivors Pant & Kamada, Hiroshima J. Med. Sci. 26, 149-154 (1977) Chernobyl clean up workers Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561 (1994) Children exposed after Chernobyl Emerit et al., Mutation Res. 373, 47-54 (1997) CF-Nelson rats Fagnet et al., Cancer Genet. Cytogenet. 12, 73-83 (1984) Patients with chromosome fragility syndromes Bloom syndrome, Fanconi anemia, XP and AT
  • 34. The dilemma for radiation protection: what is the scientific basis for radiation standards to protect the public from exposures to low levels of ionizing radiation (<0.1 Sv) where there are considerable uncertainties in the epidemiological data. Radiation Related Cancer Risk A-bomb Survivor data Supra-linearity LNT Sub-linearity Background .01 .05 .1 1.0 4.0 10 100 Dose (Sv) Hormesis
  • 35. Linear Non-Threshold is a Model/Hypothesis: As such it has been used and abused! Goal: public and worker protection Assumes: Correctly that Tissues/organs differentially sensitive Risk varies with Age Sex Socio economic status Diet and lifestyle Genetic makeup and race Dose and dose rate Radiation quality
  • 36. Questions: How to design a system that limits risk? How do we assign a potential human health risk? Caveats: This system must take into account : The most sensitive organ (breast)*? The most sensitive individual*? * Ethical and legal questions Radiation Radiation sensitive resistant Where do you draw this line for regulatory purposes?
  • 37. Extrapolation From Experimental Systems: Cells tissues organs man What does in vitro cell culture tell us about a response in humans? What do in vivo models tell us about a response in humans - how do you extrapolate from an an animal model to the human population? Should you?
  • 38. How do you communicate radiation risk when the “so called experts” do not agree? Disasters/crises make the news! The public reads/listens to the news. The public votes for politicians Politicians dictate policy Regulators have to implement the policy So where is the science? Lets take for example the increasing use of CT scans
  • 39. Brenner & Hall; “Computed tomography - An increasing source of radiation exposure” NEJM 357, 2277-2284 (2007) Scott, Sanders, Mitchel & Boreham; “CT scans may reduce rather than increase the risk of cancer” J. Amer. Phys & Surg. 13, 8-11 (2008)
  • 40. What About in the Low Dose Region? BEIR VII cited 1386 peer reviewed publications French Academie des Sciences cited 306 publications Overlap in publications cited = 68
  • 41. My thoughts. Epidemiology is unlikely to provide definitive information - always “uncertainty”. Radiobiology - mechanisms not risk. The current system works - mortality data from nuclear power workers - “healthy workers” Hard to fault regulatory bodies for endorsing the middle ground of a LNT cancer risk model Life is dangerous - keep radiation in perspective.
  • 42. OK - but given ionizing radiation is probably the best studied human carcinogen, how can we understand its mechanism of action? The Pacific Northwest National Laboratories Integrated Systems Biology Approach to Understanding Potential Effects Associated with Exposure to Ionizing Radiation.
  • 43. Why PNNL? Established effort enables system’s biology To understand organisms from a “systems perspective” we must integrate experiments, analysis and modeling in a recursive manner Hypothesis Analysis Experiment Computation and High-throughput information technologies management
  • 44. What is Systems Biology? The quantitative study of biological networks and pathways as integrated systems rather than as a set of isolated parts. Requires a long term investment in: Expertise biologists, chemists, physicists instrumentation & applied technology specialists mathematicians & computational scientists skilled laboratory technicians Time - infrastructure and expertise Technologies & development Ego suppression
  • 45. A System Is A Result Of Interacting Parts: An “interesting” part is one for which the consequences of interaction is non-trivial The sum of the system is greater than the sum of the parts. Biological systems are defined by multiple redundant and interdependent signaling networks and metabolic pathways 52
  • 46. Context Cannot Be Accurately Predicted Without Multiple Sources Of Data Well-designed studies with appropriate controls Gene expression data does not predict protein abundance Protein abundance data does not predict protein function Single time points do not provide directionality for correlation to functional outcomes Network reconstruction requires heterogeneous data for dose and dose rate-dependent and temporal 53 measurements
  • 47. Integrated Data Management Data Integration and Analysis Data Discovery (finding what is stored) Data Storage
  • 48. Key Event Networks connect molecular networks to population dynamics 55 Edwards & Preston (2008), Tox Sci, 106(2):312-318
  • 49. Hopefully PNNL’s systems radiation biology program will contribute to understanding the long term health effects of exposure to ionizing radiations But even if we do - will protection standards ever be based on scientific evidence?
  • 50. And you  don’t  believe the  media ??
  • 51. Quiz: Which one is the child of radiation exposed parent?
  • 52. Comments and Questions? wfmorgan@pnl.gov